title: Hcrtr1 and 2 signaling differentially regulates depression-like behaviors.
abstract: The orexin/hypocretin system has the potential to significantly modulate affect, based on both the neuroanatomical projection patterns of these neurons and on the sites of orexin receptor expression. However, there is little data supporting the role of specific orexin receptors in the modulation of depression-like behavior. Here we report behavioral profiling of mice after genetic or pharmacologic inhibition of hcrtr1 and 2 receptor signaling. Hcrtr1 null mice displayed a significant reduction in behavioral despair in the forced swim test and tail suspension test. Wild-type mice treated with the hcrtr1 antagonist SB-334867 also displayed a similar reduction in behavioral despair. No difference in anxiety-like behavior was noted following hcrtr1 deletion. In contrast, hcrtr2-null mice displayed an increase in behavioral despair with no effect on measures of anxiety. These studies suggest that the balance of orexin action at either the hcrtr1 or the hcrtr2 receptor produces an anti-depressant or pro-depressant like effect, depending on the receptor subtype activated.
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, West Point, PA, USA. Michael.Scott@UTSouthwestern.edu
authors.forename: Michael M
authors.initials: MM
authors.lastname: Scott
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Marcus
authors.forename: Ami
authors.initials: A
authors.lastname: Pettersen
authors.forename: Shari G
authors.initials: SG
authors.lastname: Birnbaum
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Scammell
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Michael
authors.initials: M
authors.lastname: Lutter
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics; D001583:Benzoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013550:Swimming / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D009287:Naphthyridines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea